Levetiracetam-Induced Parkinsonism: A Short Case Series

Dear Editor,

Levetiracetam is one of the most widely used antiseizure medications (ASMs) and is generally considered a relatively safe drug. Here, we report five cases of levetiracetam-induced parkinsonism (LIP) to raise awareness among physicians about this unusual adverse effect, which has not been reported in clinical trials. Patients who developed parkinsonism due to exposure to levetiracetam and were on stable drug regimens at the time of levetiracetam initiation were enrolled. All patients satisfied the following criteria for drug-induced parkinsonism: 1. presence of at least two of the four cardinal signs of parkinsonism – rest tremor, bradykinesia, rigidity, and postural imbalance; 2. symptoms beginning within 6 months of starting the offending drug; 3. no parkinsonian symptoms before introduction of the offending drug; and 4. symptom resolution within 6 months after discontinuing the offending drug.[1] Those on any other medications known to cause parkinsonism and those with any confounding factors that may precipitate subclinical parkinsonism, like septicemia, hyponatremia, or other metabolic derangements, were excluded. They underwent thorough history taking, neurologic evaluation, and magnetic resonance imaging (MRI) of the brain. We did not perform any functional imaging with positron emission tomography or single-photon emission computed tomography scans for dopamine uptake in our patients due to financial constraints and their unavailability in our hospitals. Informed consent was obtained from all patients. The study protocol was reviewed and approved by the institution’s ethics committee on May 2, 2024. Data were recorded using Excel^™ and analyzed using appropriate descriptive statistics.

We had five cases of LIP over 3 years. There were three females and two males with ages ranging from 20 to 83 years (median 36, interquartile range [IQR] (26.5 – 67.5; 41)). Bradykinesia and rigidity were present in all patients, while tremor was notably absent. The median duration of levetiracetam exposure before the onset of bradykinesia was 8 (IQR 3) weeks (range 6–12 weeks). The median dose of levetiracetam was 1000 mg/day. The mean time for resolution of parkinsonian symptoms after discontinuation of the drug was 4.2 ± 1.1 weeks. All five patients experienced complete resolution of parkinsonism following cessation of levetiracetam. Herein, we present details of two cases, while a summary of all five cases is provided in Table 1.

Table 1.

Demographic and clinical characteristics of patients with levetiracetam-induced parkinsonism

Characteristics	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
Type of epilepsy	Focal	Focal seizure	Generalized	Focal	Generalized
Age/sex	36/Female	83/Male	33/Female	20/Male	52/Female
Duration of levetiracetam before the onset of parkinsonian symptoms	8 weeks	12 weeks	8 weeks	6 weeks	8 weeks
Dose of levetiracetam	500 mg bid	500 mg bid	1000 mg bid	1000 mg OD	500 mg bid
Time to resolution of bradykinesia after stopping levetiracetam	4 weeks	4 weeks	3 weeks	6 weeks	4 weeks
Concomitant drugs	Acenocoumarol	Aspirin/amlodipine/metoprolol/prazosin/insulin	None	None	None

bid: twice daily, OD: once a day

A 36-year-old woman diagnosed with cerebral venous thrombosis was undergoing treatment with acenocoumarol and levetiracetam (500 mg twice daily). After 2 months, she presented with symptoms of slow gait and imbalance. On examination, she exhibited mask-like facies, bradykinesia, and rigidity, with no tremor. MRI of the brain revealed no basal ganglia involvement. She was not taking any antipsychotics or medications known to cause parkinsonism. Levetiracetam was discontinued, while acenocoumarol treatment was continued. At a follow-up visit 4 weeks later, her symptoms of slow gait and imbalance had completely resolved.

A 33-year-old woman presented with infrequent bilateral tonic–clonic seizures (BTCS) lasting 5 years. She had been on sodium valproate for the same duration and achieved seizure-free status for 3 years with normal findings of interictal electroencephalogram and MRI of the brain. Consequently, valproate was gradually tapered and discontinued. However, following discontinuation, she experienced clusters of BTCS. After receiving a loading dose of 2 g of levetiracetam, she was maintained on 1000 mg twice daily. Two months later, she developed decreased facial expressions, bradykinesia, restlessness, and intermittent dystonic movements of the tongue for a week. She was not taking any other medications, and routine blood tests and brain MRI were normal. Levetiracetam was discontinued and was transitioned to lacosamide. Her parkinsonian symptoms completely resolved within 3 weeks.

Parkinsonism is not recognized as a side effect of levetiracetam and has not been reported in clinical trials. However, emerging evidence suggests that levetiracetam has the potential to induce parkinsonism. In an open-label study investigating levetiracetam’s impact on reducing chorea in Huntington’s disease (HD) patients, Zesiewicz et al.[2] observed parkinsonism in two out of nine cases. Similarly, Gatto et al.[3] described a case of a 36-year-old man with HD who developed parkinsonism following levetiracetam treatment for controlling chorea. Lyons and Pahwa[4] reported exacerbation of parkinsonism, particularly rigidity and bradykinesia, in eight out of nine Parkinson’s disease (PD) patients. In addition, a recent study utilizing health-care data from UK Biobank, involving 1433 PD patients and 8598 matched controls, aimed to investigate the association between prescribed ASMs and PD.[5] This study found levetiracetam to have an odds ratio of 3.02 (1.51–6.05) for subsequent PD. We have summarized all reported cases of LIP in Table 2.

Table 2.

Reported cases of LIP

Study	No. of patients with LIP	Age (years)/gender (M/F)	Mean dose of LEV (mg/day)	Parkinsonian symptoms on LEV	Time to resolution after stopping LEV
Zesiewicz et al.[2] (case series)	2	51.9±9.3 (Not specified)	2583.3±1020.6	Rest tremors, increased rigidity, bradykinesia, imbalance, stooped axial posture, and hypophonia	7 days
Zesiewicz et al.[6] (case series)	1	58/M	750	Resting tremors, shuffling gait, increased rigidity, imbalance, and lethargy	7 days
Gatto et al.[3] (case report)	1	36/M	1000	Dysarthria, extrapyramidal rigidity, somniloquy, and unusual movements of all four limbs during sleep	9 days (Symptoms improved as LEV was tapered to 250 mg/day)
Lyons and Pahwa[4] (case series)	8	65 (51–78)/5 M/3 F	1097.2±585.6	Increased off-time, sudden off-time, balance difficulties, increased tremor, rigidity, and freezing	Not specified

F: female, LEV: levetiracetam exact, LIP: levetiracetam-induced parkinsonism, M: male

The exact mechanisms through which levetiracetam may induce parkinsonism remain unclear. Levetiracetam may cause a reduction in dopamine release by its action on Synaptic vesicle glycoprotein 2A (SV2A) in dopaminergic neurons of the pars compacta of substantia nigra.[6] Levetiracetam also inhibits “L”-type calcium channels in dopaminergic neurons, which are necessary for pacemaking activity.[7,8] Similar to valproate, levetiracetam is known to increase oxidative stress on cells, which is implicated in neurodegeneration in the dopaminergic system.[9]

The lack of recognition of LIP may stem from its rarity or could be attributed to a cognitive bias (“the eye sees only what the mind knows”). Studies have explored the role played by levetiracetam and its interference with dopaminergic transmission in relation to neuropsychiatric adverse effects and the possibility of a genetic predisposition to it. One study found a higher incidence of adverse psychotropic side effects of levetiracetam in epilepsy patients carrying genetic variants associated with decreased dopaminergic activity, such as rs1611115 (dopamine beta-hydroxylase), rs4680 (catechol-O-methyltransferase), and rs1800497 (dopamine receptor D2-associated ANKK1 TAQ-1A).[10] Extrapolating from this, an underlying genetic predisposition may explain LIP.

Physicians need to have a high index of suspicion to identify LIP and need to be careful not to mislabel them as idiopathic in patients receiving levetiracetam. As the exact prevalence of this side effect is unknown, larger-scale epidemiologic studies across multiple centers are needed. There is a need for basic research and genetic studies to elucidate the molecular mechanisms and genetic factors contributing to the development of LIP. This article aims to raise awareness among clinicians about this unusual and unrecognized side effect of levetiracetam.

Declaration of patient consent

The authors certify that due informed consent was taken from the patients as per the guidelines of the Institutional Review Board for writing and publishing the clinical details. Approval by the Institutional Ethics Committee for this study was received on May 4, 2024.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.